Exocytosis is important for the survival, growth and functions of all eukaryotic cells, and is centrally involved in many physiological processes ranging from neurotransmission to organogenesis. Exocytosis is mediated by transport, docking and fusion of secretory vesicles carrying cargos to the plasma membrane. The exocyst is an evolutionarily conserved octameric protein complex essential for exocytosis. Malfunction of the exocyst has been linked to diabetes, Autosomal Polycystic Kidney Diseases and cancer. We have recently solved the structure of the fully assembled exocyst complex by cryo-electron microscopy and identified two four-helix bundles, termed ?CorEx?, that potentially mediate the core assembly of the exocyst complex. In this proposal, we will first study the molecular interactions and high-resolution structure of the CorEx taking a multipronged approach that combines biochemistry, biophysics, crystallography, and microscopic imaging. We will also determine the function of the exocyst complex in SNARE assembly and membrane fusion using in vitro reconstituted liposome systems. Finally, we will examine the functional implication of a newly identified interaction between the exocyst and EHD proteins, which function in the generation of tubular vesicular carriers from the endosomal compartments. We will further examine the regulation of the exocyst-EHD interaction by RalA, a small GTPase that controls endosomal recycling to the plasma membrane in response to growth factor signaling. Our work will not only help elucidate the mechanisms of exocytosis at the molecular level, but also shed light to a number of diseases such as diabetes and cancer.

Public Health Relevance

Exocytosis is implicated in many physiological processes such as embryogenesis, epithelial cell polarization, and neural transmission. The exocyst, an evolutionarily conserved octameric protein complex, plays an important role in exocytosis. Studying the basic function of the exocyst complex is essential for elucidating the molecular mechanisms of exocytosis and will lay the foundation for the understanding of many human diseases such as diabetes and cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Ainsztein, Alexandra M
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University of Pennsylvania
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Mei, Kunrong; Li, Yan; Wang, Shaoxiao et al. (2018) Cryo-EM structure of the exocyst complex. Nat Struct Mol Biol 25:139-146
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